PEG-conjugated bovine haemoglobin enhances efficiency of chemotherapeutic agent doxorubicin with alleviating DOX-induced splenocardiac toxicity in the breast cancer.

Doxorubicin (DOX) is an effective chemotherapeutic agent widely used for cancer treatment. However, hypoxia in tumour tissue and obvious adverse effects particularly cardiotoxicity restricts the clinical usage of DOX. Our study is based on the co-administration of haemoglobin-based oxygen carriers (HBOCs) and DOX in a breast cancer model to investigate HBOCs' ability to enhance chemotherapeutic effectiveness and its capabilities to alleviate the side effects induced by DOX. In an in-vitro study, the results suggested the cytotoxicity of DOX was significantly improved when combined with HBOCs in a hypoxic environment, and produced more γ-H2AX indicating higher DNA damage than free DOX did. Compared with administration of free DOX, combined therapy exhibited a stronger tumour suppressive effect in an in-vivo study. Further mechanism studies showed that the expression of various proteins such as hypoxia-inducible factor-1α (HIF-1α), CD31, CD34, and vascular endothelial growth factor (VEGF) in tumour tissues was also significantly reduced in the combined treatment group. In addition, HBOCs can significantly reduce the splenocardiac toxicity induced by DOX, according to the results of the haematoxylin and eosin (H&E) staining and histological investigation. This study suggested that PEG-conjugated bovine haemoglobin may not only reduce the hypoxia in tumours and increase the efficiency of chemotherapeutic agent DOX, but also alleviate the irreversible heart toxicity caused by DOX-inducted splenocardiac dysregulation.

Phenoxyaromatic Acid Analogues as Novel Radiotherapy Sensitizers: Design, Synthesis and Biological Evaluation.

Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and chemotherapy. However, the non-sensitivity of tumor cells in the hypoxic area of solid tumors to radiotherapy may cause radioresistance. Therefore, radiotherapy sensitizers that increase the oxygen concentration within the tumor are promising for increasing the effectiveness of radiation. Inspired by hemoglobin allosteric oxygen release regulators, a series of novel phenoxyacetic acid analogues were designed and synthesized. A numerical method was applied to determine the activity and safety of newly synthesized compounds. In vitro studies on the evaluation of red blood cells revealed that compounds 19c (∆P50 = 45.50 mmHg) and 19t (∆P50 = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P50 = 36.40 mmHg). Preliminary safety evaluation revealed that 19c exhibited no cytotoxicity towards HEK293 and U87MG cells, while 19t was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that 19c exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that 19c was orally available.

Effects of different plasma expanders on rats subjected to severe acute normovolemic hemodilution.

BACKGROUND: Plasma expanders are widely used for acute normovolemic hemodilution (ANH). However, existing studies have not focused on large-volume infusion with colloidal plasma expanders, and there is a lack of studies that compare the effects of different plasma expanders. METHODS: The viscosity, hydrodynamic radius (Rh) and colloid osmotic pressure (COP) of plasma expanders were determined by a cone-plate viscometer, Zetasizer and cut-off membrane, respectively. Sixty male rats were randomized into five groups with Gelofusine (Gel), Hydroxyethyl Starch 200/0.5 (HES200), Hydroxyethyl Starch 130/0.4 (HES130), Hydroxyethyl Starch 40 (HES40), and Dextran40 (Dex40), with 12 rats used in each group to build the ANH model. ANH was performed by the withdrawal of blood and simultaneous infusion of plasma expanders. Acid-base, lactate, blood gas and physiological parameters were detected. RESULTS: Gel had a lower intrinsic viscosity than HES200 and HES130 (P < 0.01), but at a low shear rate in a mixture of colloids, red cells and plasma, Gel had a higher viscosity (P < 0.05 or P < 0.01, respectively). For hydroxyethyl starch plasma expanders, the COP at a certain concentration decreases from 11.1 mmHg to 6.1 mmHg with the increase of Rh from 10.7 nm to 20.2 nm. A severe ANH model, with the hematocrit of 40% of the baseline level, was established and accompanied by disturbances in acid-base, lactate and blood gas parameters. At the end of ANH and 60 min afterward, the Dex40 group showed a worse outcome in maintaining the acid-base balance and systemic oxygenation compared to the other groups. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) decreased significantly in all groups at the end of ANH. The DBP and MAP in the Dex40 group further decreased 60 min after the end of ANH. During the process of ANH, the Dex40 group showed a drop and recovery in SBP, DBP and MAP. The DBP and MAP in the HES200 group were significantly higher than those in the other groups at some time points (P < 0.05 or P < 0.01). CONCLUSION: Gel had a low intrinsic viscosity but may increase the whole blood viscosity at low shear rates. Rh and COP showed a strong correlation among hydroxyethyl starch plasma expanders. Dex40 showed a worse outcome in maintaining the acid-base balance and systemic oxygenation compared to the other plasma expanders. During the process of ANH, Dex40 displayed a V-shaped recovery pattern for blood pressure, and HES200 had the advantage in sustaining the DBP and MAP at some time points.

The P50 value detected by the oxygenation-dissociation analyser and blood gas analyser.

Oxygen tension at 50% haemoglobin saturation (P50), which reflects the degree of peripheral oxygen offloading and tissue oxygenation, plays an important role in the diagnosis and treatment of disease, as well as in transfusion research. Blood gas analysers are commonly used in clinical and obtain P50 values through complex calculations and analysis. Oxygenation-dissociation analysers are specially designed to record the oxygen dissociation curves and obtain P50 values of whole blood, red blood cells (RBCs), and stroma-free haemoglobin. However, whether the two equipment obtain comparable data is still uncertain. Herein, we used both equipment to detect P50 values of blood and stroma-free haemoglobin from human and bovine sources, venous and arterial blood of beagle and rat, and stored rat blood. For human blood, both analysers yielded similar data. P50 of the stroma-free haemoglobin and bovine blood could only be properly detected by oxygenation-dissociation analysers. Blood gas analysers showed different P50 values, while oxygenation-dissociation analysers got similar P50 values for arterial and venous samples. Oxygenation-dissociation analysers distinguished changes in P50 values during RBCs storage. Compared with the blood gas analysers, oxygenation-dissociation analysers had a stronger detection capability in P50 measurement with regard to both sample types and species.

Characterization and Biosafety Evaluation of Hemoglobin-Based Oxygen Carriers Coated with Polydopamine.

Hemoglobin-polydopamine particles (Hb-PDA) have shown high stability, with polydopamine (PDA) serving as a protective layer and antioxidant. However, the effects of the PDA coating on the properties and in vivo biosafety of Hb-PDA remain unclear. This work was conducted to characterize Hb-PDA and evaluate its biosafety. Hb-PDA exhibited negative surface charge and their infusion did not cause blood immunotoxicity or significant tissue injury. Hb-PDA were not phagocyted after co-incubation with macrophages for 3 h. Moreover, the particles showed the highest accumulation in the lungs, and a prolonged retention in major organs. It was also found that the particles were cleared by macrophages in splenic tissue and Kupffer cells in hepatic tissue. In summary, this research showed that Hb-PDA has high dispersion stability, low in vivo toxicity, and extended retention, illustrating its potency as a biosafe oxygen carrier.